GPR40 novel agonist SZZ15-11 regulates glucolipid metabolic disorders in spontaneous type 2 diabetic KKAy mice
G protein-coupled receptor(GPR)40,as one of GPRs family,plays a potential role in regulating glucose and lipid metabolism.To study the effect of GPR40 novel agonist SZZ15-11 on hyperglycemia and hyperlipidemia and its potential mechanism,spontaneous type 2 diabetic KKAy mice,human hepatocellular carcinoma HepG2 cells and murine mature adipocyte 3T3-L1 cells were used.KKAy mice were divided into four groups,vehicle group,TAK group,SZZ(50 mg·kg-1)group and SZZ(100 mg·kg-1)group,with oral gavage of 0.5％sodium carboxymethylcellulose(CMC),50 mg·kg-1 TAK875,50 and 100 mg·kg-1 SZZ15-11 respectively for 45 days.Fasting blood glucose,blood triglyceride(TG)and total cholesterol(TC),non-fasting blood glucose were tested.Oral glucose tolerance test and insulin tolerance test were executed.Blood insulin and glucagon were measured via enzyme-linked immunosorbent assay(ELISA).After mice's execution,liver tissue was harvested to test TG and TC content.Then pathological morphology of liver was observed through hematoxylin-eosin(HE)staining,and the lipid metabolism relative signal pathway was analyzed by Western blot and RT-PCR.The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College.At the same time,Akt phosphorylation level in HepG2 cells and adiponectin in 3T3-L1 cells treated with TNFα were measured with Western blot.The results show that SZZ 15-11 not only decreased blood glucose and lipid,improved insulin sensitivity,but also increased fasting blood glucagon and promoted insulin secretion after glucose loading in KKAy mice.Additionally,SZZ15-11 alleviated hepatic steatosis and liver dysfunction in KKAy mice.In liver tissue,SZZ15-11 increased AMPKα phosphorylation level and cholesterol metabolism relative gene Abcg8 transcription.In HepG2 cells,SZZ15-11 increased Akt phosphorylation level.In adipocyte 3T3-L1,SZZ15-11 recovered the decreased adiponectin expression by TNFα.This study proved that GPR40 agonist SZZ 15-11 could be a candidate compound for regulating glucolipid metabolic disorder.
G protein-coupled receptor 40type 2 diabetesglucose and lipid metabolismhepatic steatosisinsulin resistance
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